The "potential (and differential) effect on blood pressure elevation requires caution in the use [of COX 2s] and warrants further investigation," conclude researchers led by Henry Krum, MBBS, PhD, FRACO, head of the clinical pharmacology unit at Monash University in Melbourne, Australia. "Clinicians need to weigh the risks of improved gastrointestinal safety versus potential hazards of developing elevated blood pressure when considering the use of these agents, especially in the elderly population."
According to the analysis, COX-2s, or coxibs, caused a weighted mean difference (WMD) in systolic blood pressure (BP) compared to placebo and traditional NSAIDs of 3.85 and 2.83 mm Hg, respectively. These elevations in systolic BP may be clinically significant with respect to cardiovascular (CV) risk. Furthermore, the results suggest that the elevations are accompanied by a potential widening of pulse pressure (the difference between systolic and diastolic BP), a phenomenon that was identified as a CV risk factor in the Framingham Study.2
The clinical significance of these increases in BP was illustrated by a trend toward greater risk for hypertension associated with use of coxibs. These patients had a 61% increase in relative risk of hypertension compared with those taking placebo and a 25% increase compared with patients taking traditional NSAIDs, although these findings were not statistically significant. These results are consistent with both coxibs and nonselective NSAIDs causing prostaglandin inhibition and possessing antinatriuretic and vasoconstrictor properties.
Differences Among Coxibs Detected
There were differences noted between the COX-2 inhibitors. "Rofecoxib (VioxxR) appears to confer a greater risk of developing hypertension and clinically important elevations in both systolic and diastolic blood pressure compared with celecoxib (CelebrexR)," study authors note. The WMD in systolic BP between rofecoxib and celecoxib was measured at 2.83 mm Hg.
The 19 studies in the meta-analysis encompassed 45,451 patients. Of these, 29,824 had osteoarthritis and 15,627 had rheumatoid arthritis. Trials involving coxib versus placebo comprised 5786 patients, while coxib versus NSAID trials had 40,888 patients and rofecoxib versus celecoxib had 2833 patients. COX-2 drugs used in studies also included etorioxib (ArcoxiaR). The most commonly used nonselective NSAID was naproxen.
The data addressing risk for hypertension in patients using coxibs complements studies examining their association with myocardial infarction. "One of the issues is: Do these drugs raise blood pressure more than the standard NSAIDs? And, the other question is: Are those people who have heart attacks the subgroup who have the worse elevation in blood pressure? There is some evidence that [the latter] could be the case," Matthew D. Breyer, MD, the Catherine McLaughlin Hakim Professor of Medicine and Molecular Physiology and Biophysics at Vanderbilt University Medical School in Nashville, Tennessee, tells CIAOMed.
"The idea being that it takes 18 months to develop risk for myocardial infarction is consistent with the idea that chronic vascular damage, perhaps from hypertension, contributes to this risk," Dr. Breyer observes.
"I would be surprised if those people who did have blood pressure increases did not comprise the group of patients who had increased risk of heart attack," he continues. "I think that physicians need to be aware of the long-term effects of COX-2s and NSAIDs on blood pressure and treat [these patients] more aggressively."
"I think it is still an open question whether a COX-2 inhibitor with the same pharmacokinetics will raise blood pressure any differently than nonselective NSAIDs," Dr. Breyer adds. Many of the these questions, and more, will be raised later this week at the upcoming federal Food and Drug Administration advisory meeting on the risks/benefits of coxibs.
References:
1. Aw T-J, Haas SJ, Liew D, Krum H. Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure. Arch Intern Med. 2005;165:1-7.
2. Kannel WB. Fifty years of Framingham Study contributions to understanding hypertension. J Hum Hypertens. 2000;14:83-90.